Highlights from Recent Cancer Literature
Journal: Cancer Research (2011)

Daldrup-Link HE, Golovko D, Ruffell B, Denardo DG, Castaneda R, Ansari C, et al. MRI of tumor-associated macrophages with clinically applicable iron oxide nanoparticles. Clin Cancer Res 2011;17:5695–704.Tumor-associated macrophages (TAM) are critically linked to solid tumor development through their ability to promote angiogenesis, tissue remodeling, anddelivery of survival factors to neoplastic cells and their expression of powerful mediators that inhibit antitumor immunity. In breast cancer, macrophage presence has been found to represent an independent prognostic indicator correlating with survival, as well as pathologic response to conventional cytotoxic therapy. As such, therapeutics have been developed that are designedto block macrophage infiltration of tumorsvia blockade of the colony-stimulating factor-1 (CSF1)/CSF1 receptor (CSF1R) pathways that are critical for macrophage recruitment andsurvival. With the entry of these drugs into the clinic, a diagnostic assay with capability to quantify TAM presence in tumors would be advantageous, not only for identifying patients likely to benefit from CSF1/CSF1R antagonists but also to monitor patients on therapy for evidence of therapeutic response. Daldrup-Link and colleagues describe a unique ex vivo imaging approach for monitoring TAMs in tumors via magneticresonance (MR) imaging using an ultra-small superparamagnetic iron oxide nanoparticle (USPIO) approved by the U.S. Food and Drug Administration that has traditionally been used for treatment of iron deficiency. In tumors with increased microvascular permeability, USPIOs gradually leak across hyperpermeable vessels into tumor interstitium, where they exert a combined positiveMRsignal effect on T1-weightedMRimages and a negative MR signal effect on T2-weighted MR images. Thus, in mammary tumors heavily infiltrated by TAMs, the USPIO was selectively taken up by the TAMs and thereby provided an effective MR contrast agent. Treatment of mice with a CSF1 neutralizing monoclonal antibody that reduced TAM infiltration by approximately 50% greatly reduced the MR contrast enhancement producedby the USPIO, providing preclinical evidence that this novel imaging approachmayallow real-time monitoring of patients receiving TAM-targeted therapies and identify patients likely to benefit from these novel agents.Brough R, Frankum JR, Sims D, Mackay A, Mendes-Pereira AM, Bajrami I, et al. Functional viability profiles of breast cancer. Cancer Discovery 2011;1:260–73.Genomic sequencing continues to identify new genetic lesions in cancer, offering challenges and opportunities for therapeutic targeting. To understand the functional implications of targeting many genetic lesions in breast cancer, Brough and colleagues with loss of Rb and p107, leading to upregulation of the cyclindependent kinase inhibitor p21 in the mouse, with inhibition of mir-17 ∼ 92 also driving p21 in human retinoblastoma cells. These data identify a new mechanism underlying the oncogenicity of this complex microRNA cluster.Viatour P, Ehmer U, Saddic LA, Dorrell C, Andersen JB, Lin C, et al. Notch signaling inhibits hepatocellular carcinoma following inactivation of the RB pathway. J Exp Med 2011 Aug 29. [Epub ahead of print].Although viral infection and chemical damage are known risk factors for human hepatocellular carcinoma (HCC), the cellular and molecular mechanisms of the development of this lethal cancer remain uncertain. Many studies have reported that the tumor-suppressive retinoblastoma (RB) pathway is typically inactivated during the early stages of carcinogenesis, indicating a role for one or another of the RB family members. To address this possibility, the investigators generated Rb family triple knockout (TKO) mice via intrasplenic injections of adenovirus-expressing Cre recombinase in conditional TKO mice (cTKO; Rb lox/lox; p130 lox/lox; p107−/−). The TKO mice developed multiple liver tumors within 3 to 4months, all of which exhibited histopathology, protein markers, and gene expression patterns consistent with human HCC. Moreover, in TKO mice, specific expansion of small populations of liver stem/progenitor cells prior to cancer development was evident, indicating that the RB pathway may prevent HCC development by maintaining adult liver stem cells in a quiescent state. In addition, a Notch pathway signature was identified that strongly predicted survival in a cohort of 53 patients, thus supporting a model whereby activation of the Notch pathway via E2F transcription factors serves as a negative feedback mechanismslowing HCC growth. Although this feedback mechanism is not sufficient to prevent cancer initiation, activation of Notch may significantly slow expansion of tumor cells in vivo.Conkrite K, Sunby M, Mukai S, Thomson JM, Mu D, Hammond SM, et al. miR-17 ∼ 92 cooperates with RB pathway mutations to promote retinoblastoma. Genes Dev 2011;25:1734–5..The mir-17 ∼ 92 cluster was one of the first microRNAs established as contributing to cancer, with miR-19 in this cluster targeting PTEN and driving activation of phosphoinositide 3-kinase. Conkrite and colleagues demonstrate the overexpression of this cluster in retinoblastoma, a rare childhood cancer driven by loss of the RB tumor suppressor. Theywent on to demonstrate amplification of this cluster in a mouse model of retinoblastoma, driven by loss of Rb and the Rb family member p107. Forced expression of miR-17 ∼ 92 in the setting of Rb and p107 loss led to increased penetrance for retinoblastoma in mice, associated with metastasis within the brain. Expression of this cluster cooperated expression and NeuN expression, supporting a relationship between AEG-1 expression and neurotoxicity. These provocative findings suggest that targeted inhibition of AEG-1 might translate into suppressed GBM pathogenicity resulting from inhibition of EAAT2 expression, thereby preventing excitotoxicity through glutamate-induced neuronal death.Lee SG, Kim K, Kegelman TP, Dash R, Das SK, Choi JK, et al. AEG-1 promotes glioma-induced neurodegeneration by increasing glutamate excitotoxicity. Cancer Res; Published OnlineFirst August 18, 2011; doi:10.1158/0008-5472.CAN-11-0782.Glioblastoma multiforme (GBM; grade IV astrocytoma) presents as an aggressive, invasive, and destructive cancer that is essentially resistant to current treatments based on cytotoxic approaches targeting replicating DNA, such as chemotherapy or radiotherapy. GBMs are rapidly proliferating neoplasms that can elicit neurodegeneration. Astrocyte-elevated gene 1 (AEG-1) is an oncogene overexpressed in more than 90% of central nervous system tumors that has been found to contribute directly to the invasive and pathogenic propertiesof GBM. Lee and colleagues document a direct association between AEG-1 expression and neurodegeneration and the mechanism underlying the effect of this oncogene on neuron toxicity through regulation of the major regulator of glutamate transport in astrocytes, excitatory amino acid transporter-2 (EAAT2). A comparison of expression of AEG-1 and EAAT2 in samples of normal brain and GBM confirmed a strong negative Pearson correlation. Through aseries of gain- and loss-of-function experiments in both normal primary human fetal astrocytes and GBM cells, AEG-1 was shown to repress EAAT2 expression on a transcriptional level by inducing YY1 activity, which subsequently inhibited CREB-binding protein function normally operating as a coactivator on the EAAT2 promoter. In addition, AEG-1—mediated EAAT2 repression promoted a reduction of glutamate uptake by glial cells, thereby promoting neuronal cell death (excitotoxicity). An examination of patient samples confirmed a negative correlation between AEG-1 performed an RNA interference screen in 34 breast cancer—derived cell lines. Using an siRNA library targeting 714 kinases or kinaserelated genes, they screened cell lines for loss of viability. These studies identified genetic dependencein both estrogen receptor—positive cancer [dependent on an uncharacterized aarF domain—containing protein kinase (ADCK2)] and PTEN-deficient cell lines (dependent on mitotic checkpoint kinases), both of which represent therapeutic targets in breast cancer.Xue W, Meylan E, Oliver TG, Feldser DM, Winslow MM, Bronson R, et al. Response and resistance to NF-kB inhibitors in mouse models of lung adenocarcinoma. Cancer Discovery 2011;1:236–47.Lung adenocarcinoma is a leading cause of death worldwide. In previous studies, the Jacks group pointed to a significant role for NF-κB signaling for lung tumorigenesis, indicating that selective inhibition of the NF-κB pathway may represent a tractable therapeutic option. To test this assertion, these investigators examined the potential role of lowmolecular-weight NF-κB inhibitors for treatment of lung cancer using their elegant in vivo mouse models. Provocatively, bortezomib, a proteasome inhibitor known to target the NF-κB pathway, as well as other pathways, induced lung tumor regression and prolonged survival of Kras/p53 mutant mice through a mechanism involving increased apoptosis of tumor cells.However, after prolonged therapy, the tumors showed resistance. Similarly, the initialtherapeutic efficacy of another NF-κB inhibitor, Bay-117082, was also followed by development of acquired resistance. These findings suggest that targeted inhibition of NF-κB may represent a useful therapeutic approach for some types of lung cancer. However, such a strategy is likely to require delivery in combination with conventional cytotoxic therapies, or alternatively, in combination with agents blocking other critical parameters of tumor cell proliferation.Note: Breaking Advances are written by Cancer Research Editors. Readers are encouraged to consult the articles referred to in each item for full details on the findings described.